Scientists have completely sequenced the human Y chromosome for the first time, with huge implications for heath and evolution research

• Researchers published two new papers on the human Y chromosome. 
• It's the final chromosome in the human genome that researchers hadn't fully sequenced. 
• The new reference could help researchers better understand infertility and some types of cancer.

Decades ago, researchers referred to the human Y chromosome as a "functional wasteland," among other names.

A huge amount of its genome was unsequenced, and it was difficult to know how some of its protein-coding genes worked. But not anymore.

Two new papers, both published today in Nature, shed light on some of the Y chromosome's mysteries.

Each paper's results could offer new insight for research into reproduction, some types of cancer, aging, and human evolution. 

Finally mapping the Y chromosome

The first paper highlights how researchers completely sequenced an individual's Y chromosome for the first time, adding over half the genetic information that was previously missing.

Chromosomes carry DNA in the nucleus of every cell in the human body. The rungs of DNA's ladder consist of base pairs (adenine, cytosine, thymine, and guanine) of which there are about 3 billion in the complete human genome. Over 62 million of them belong to the Y chromosome. 

The new sequencing added over 30 million base pairs to fill in significant gaps in the human genome reference.

Another group of scientists sequenced an additional 43 Y chromosomes from people all over the world for the second paper to get a more complete picture of variations across individuals and populations. 

"It really took a star-studded cast of people to make sure that this was an accurate reference because we understand how important it is, every single base on that reference," said Karen Miga, one of the authors of the first study and co-founder of the Telomere-to-Telomere Consortium. 

What's so tricky about the Y chromosome? 

Most people have 22 pairs of chromosomes and two sex chromosomes, usually either XX or XY. 

The other sex chromosome, the X chromosome, has more than double the base pairs of the Y, but it was far easier to sequence.

That's because the Y chromosome is "the most complex, most repetitive chromosome," said Monika Cechova, a postdoctoral researcher at the University of California, Santa Cruz.

"The human Y chromosome is like a hall of mirrors," said Pascal Gagneux, professor of pathology and anthropology at UC San Diego, who wasn't involved in either paper.

There are tons of repeating sequences that are palindromes, reading the same forward as backward, like the words mom, peep, and kayak.

"You're just surrounded by lots of similar sequences, and you don't know in which direction they go," said Gagneaux, who is associated with one of the researchers, Evan Eichler, through the Center for Academic Research and Training in Anthropogeny.

However, understanding these palindromic regions is important because they code for processes like sperm production.

These repeating sequences also result in gene pairs that may serve as backups in case of mutation, helping genes continue to function, Cechova said.

Using an algorithm to read the sequence helped the researchers keep track of the gene copies and where they belonged.  

The repetitious Y chromosome

Further complicating the sequencing were the two satellite DNA regions that researchers didn't know much about.

"Here you had tens of millions of bases that were just seemingly repeating the same paragraph over and over," Miga said. 

The function of the long, repetitive sequences on one of the arms of the chromosome is still a mystery, but there's a better way to map them than there was 20 years ago.

A newer sequencing technique read longer chunks of DNA that were easier to piece back together than the smaller fragments geneticists used for earlier genome references.

Researchers from the NHGRI compared sequencing the Y chromosome to trying to assemble a book that had been cut into strips, where half the sentences were all exactly the same.

You don't want the same words from page 45 to end up on page 108. 

"It was always irritating knowing we were missing half the Y whenever we tried to do any reference-based analysis," Arang Rhie, a staff scientist at the National Human Genome Research Institute and the lead author on the single-sequence paper, said in a statement. 

The worldwide Y chromosome

For the single-sequence paper, researchers sequenced the Y chromosome of a single individual of European descent, known as the HG002 genome.

All human genomes share 99.9% of the same base pairs, but that 0.1% difference can have an impact on health. 

While the HG002 Y chromosome sequence provides an important baseline for genetic comparison, the second paper from the Jackson Laboratory for Genomic Medicine shows just how many variations there are between individuals.

Selected from the 1000 Genomes Project, about half the 43 individuals have African ancestry, which is important for representing genetic diversity, Gagneux said.  

Among the several dozen Y chromosomes the researchers looked at, they saw marked differences in size and structure. For example, they found a range in the number of base pairs, from 45.2 million to 84.9 million. 

Because of all the gaps in the Y chromosome genome reference, researchers haven't fully understood how the chromosome contributes to overall health.

The hope is that the new research will give scientists more knowledge about how genetic differences affect infertility, cancer, and other health concerns. 

Where and how Y chromosomes differ from one another can also help molecular anthropologists and others interested in human evolution and historical migration.

Post fertilization, most chromosomes trade DNA segments, so the resulting gametes are a mix of both parents. But Y chromosomes don't swap, passing from parent to child almost unchanged.

"It's an incredibly good tool to study what has happened in the last 10,000 years in human history and prehistory," Gagneux said.